Increase of survival benefit in advanced resectable colon cancer by extent of adjuvant treatment: results of a randomized trial comparing modulation of 5-FU + levamisole with folinic acid or with interferon-alpha

Ann Surg. 2005 Aug;242(2):178-87. doi: 10.1097/01.sla.0000171033.65639.a9.


Background: The benefit of adjuvant therapy in curatively resected lymph node-positive colon cancer was established using 5-fluorouracil (5-FU) and levamisole (LEV) for 12 months. 5-FU cytotoxicity can be modulated by folinic acid (FA) or interferon-alpha (INF-alpha). The aim of this study was to investigate the efficacy of modulating 5-FU+ LEV by either FA or IFN-alpha in the adjuvant treatment of high-risk colon cancer.

Methods: Patients with curatively resected colon cancer (stages UICC IIb and III) were stratified according to T, N, and participating center and randomized to receive a 12-month treatment using 5-FU + LEV alone or in combination with FA or IFN-alpha.

Results: A total of 855 of 904 entered patients (94.6%) were eligible. The median follow-up of all eligible patients was 4.6 years. Addition of FA to 5-FU + LEV improved recurrence-free and overall survival in comparison with 5-FU + LEV alone (P = 0.007 and P = 0.004, respectively, 1-sided). The 5-year overall survival rates were 60.5% (95% confidence interval, 54.3-66.7) and 72.0% (95% confidence interval, 66.5-77.5) for 5-FU + LEV and 5-FU + LEV + FA, respectively. Addition of INF-alpha showed a tendency to improve recurrence-free survival, however, without altering overall survival. Toxicities (WHO III + IV) were generally tolerable except one toxic death in the control arm and were observed in 9.9% of the patients receiving 5-FU + LEV alone and in 13.3% and in 30.7% of patients receiving additional FA and IFN-alpha, respectively.

Conclusions: Addition of IFN-alpha was associated with increased toxicity without markedly influencing the outcome and should therefore not be recommended for adjuvant treatment. Addition of FA increased the 5-year recurrence-free and overall survival rate by 9.3 and 11.5 percentage points, respectively. 5-FU + LEV + FA for 12 months may be an effective adjuvant treatment option for locally advanced high-risk colon cancer.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / toxicity
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / toxicity
  • Chemotherapy, Adjuvant
  • Colonic Neoplasms / mortality
  • Colonic Neoplasms / therapy*
  • Female
  • Fluorouracil / administration & dosage*
  • Fluorouracil / toxicity
  • Follow-Up Studies
  • Humans
  • Interferon-alpha / administration & dosage
  • Leucovorin / administration & dosage
  • Levamisole / administration & dosage
  • Male
  • Middle Aged
  • Patient Compliance
  • Survival Rate


  • Antimetabolites, Antineoplastic
  • Interferon-alpha
  • Levamisole
  • Leucovorin
  • Fluorouracil